Inclusion Criteria:
* Patient must be ≥ 18 years of age.
* Patients must have confirmed diagnosis of AML (excluding acute promyelocytic leukemia) based on World Health Organization classification (Arber 2016).
* Disease characteristics and allowable prior therapy:
* Patients must be evaluated for any available standard of care therapies (including induction, consolidation chemotherapy and/or transplant) and, in the opinion of the treating physician, be deemed appropriate for this experimental therapy.
* Treatment-naïve (untreated) patients will be allowed in the Expansion Phase for Regimen C (Triplet) (IMGN632 + azacitidine + venetoclax). No prior treatments with hypomethylating agents (HMAs) for MDS are allowed.
* Patients must have CD123-positive AML as confirmed by local flow cytometry (or immunohistochemistry \[IHC\]).
* Patients may have received prior CD123-targeted therapies, except IMGN632, as long as CD123 remains detectable during screening.
* Relapsed or refractory CD123-positive AML patients will be allowed to enroll in the Escalation Phase of Regimens A, B, and C (Triplet (IMGN632 + azacitidine, venetoclax, or azacitidine + venetoclax, respectively) and relapsed CD123-positive AML patients will be allowed to enroll the Expansion Phase of Regimens A-C. Note: Patients may also have received up to 2 prior lines of therapy, eg, frontline treatment (induction, consolidation \[including transplant\], and maintenance) and 1 salvage regimen.
* Patients enrolling in Regimen D must be in CR (CR/CRh/CRp/ CRi) and be MRD+ at the time of screening, confirmed by central laboratory testing. Patients may have no more than 2 prior lines of therapy (which may include stem cell transplant), ie, frontline or first salvage. Note: Fit patients who received intensive treatment (eg 3+7, HiDAC) are eligible for Regimen D Cohort D1. Unfit patients who received non-intensive treatment (eg, HMA, low dose cytarabine) are eligible for Regimen D Cohort D2.
* Previous treatment-related toxicities must have resolved to Grade 1 or baseline (excluding alopecia).
* For patients enrolling in Regimens A-D, total WBC count must \< 25 × 10\^9 cells/L. Hydroxyurea may be used to control blood counts before Cycle 1 Day 1, at the discretion of the treating physician, according to institutional practice. During the Escalation Phase in Regimens A-C, hydroxyurea may also be used during Cycle 1.
* Liver enzymes (AST and ALT) ≤ 3 × the upper limit of normal (ULN).
* Total bilirubin ≤ 1.5 × the ULN; patients with Gilbert syndrome must have total bilirubin \< 3.0 × ULN with direct bilirubin \< 1.0 × ULN at the time of enrollment.
* An estimated glomerular filtration rate (eGFR) of \> 30 mL/min/1.73 m2 or creatinine clearance of \> 30 mL/min.
* Left ventricular ejection fraction (LVEF) ≥ 45% for patients enrolling in Regimens A-D based on locally available assessment, eg, echocardiogram or other modality.
* Patients with prior autologous or allogeneic bone marrow transplant are eligible. Patients with an allogeneic transplant must meet the following conditions: The transplant must have been performed more than 120 days before the date of dosing on this study, the patient must not have active ≥ Grade 2 graft versus host disease (GvHD), or extensive chronic GvHD of any severity, and must be off all immunosuppression for at least 2 weeks prior to first dose of IMGN632.
* Participants or their legally authorized representative must voluntarily sign and date an informed consent, approved by an Institutional Review Board/Independent Ethics Committee (IRB/IEC), before performance of any study-related procedure not part of normal medical care.
* Women of childbearing potential (WCBP), defined as sexually mature women who have not undergone surgical sterilization or who have not been naturally postmenopausal for at least 12 consecutive months (ie, who have had menses any time in the preceding 12 consecutive months), must agree to use acceptable contraceptive methods while on study drug and for at least 7 months after the last dose of IMGN632.
* WCBP must have a negative pregnancy test within 3 days before the first dose of study drug.
* Male patients who are able to father children must agree to use acceptable methods of contraception throughout the study and for at least 4 months after the last dose of study drug(s).
* Patients with prior malignancy are eligible; however, the patient's malignancy must be well-controlled or stable and have completed all systemic chemotherapy and radiotherapy for the prior malignancy at least 6 months before enrollment, and all treatment-related toxicities must have resolved to ≤ Grade 1 (excluding alopecia). Note: patients with prostate cancer or breast cancer on adjuvant hormonal therapy are eligible and may or may not be on long-term maintenance treatment that is unlikely to interfere with study therapy. Note: patients with tumors with a negligible risk for metastasis or death (eg, adequately controlled basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast) are eligible.
* Patients in expansion Cohorts C1 and C2 must be considered ineligible for intensive induction therapy defined by the following:
* ≥ 75 years of age OR
* \< 75 years of age with at least one of the following co-morbidities documented within 28 days of Cycle 1 Day 1:
* ECOG performance status of 2 or 3
* History of congestive heart failure requirement treatment or ejection fraction ≤ 50% or chronic stable angina
* Diffusing capacity of the lung for carbon monoxide ≤ 65% or forced expiratory volume in 1 second ≤ 65%
* Creatinine clearance ≥ 30 mL/min to \< 45 mL/min
* Moderate hepatic impairment with total bilirubin \> 1.5 to ≤ 3.0 × ULN
* Patients in Cohort C1 and C2 must have an ECOG performance status of 0 to 2 for those ≥ 75 years of age OR 0 to 3 for \< 75 years of age.
* Patients must not be incarcerated and must be freely willing and able to provide informed consent. Examples of patients unable to freely provide informed consent may include some adults under legal protection measure (eg, under guardianship/curatorship) or unable to express their consent and select adults under psychiatric care. Investigator's discretion should be applied.
Exclusion Criteria:
* Patients who have received any anticancer therapy, including investigational agents, within 14 days (or within 28 days for checkpoint inhibitors) before drug administration on this study (hydroxyurea is allowed before beginning study treatment). Patients must have recovered to baseline from all acute toxicity from this prior therapy.
* Patients who have been previously treated with IMGN632.
* Patients with myeloproliferative neoplasm-related secondary AML are excluded from the Dose Expansion Phase of the study.
* Patients with active central nervous system (CNS) AML will be excluded. A lumbar puncture does not need to be performed unless there is clinical suspicion of CNS involvement per investigator judgement. Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS AML is allowed with the approval of the sponsor.
* Patients with a history of sinusoidal obstruction syndrome/venous occlusive disease of the liver.
* Myocardial infarction within 6 months before enrollment or New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities before study entry.
* Clinically relevant active infection including known active hepatitis B or C, HIV infection, or cytomegalovirus or any other known concurrent infectious disease that, in the judgment of the investigator, would make a patient inappropriate for enrollment into this study (testing not required).
* Patients who have undergone a major surgery within 4 weeks (or longer if not fully recovered) before study enrollment.
* Serious or poorly controlled medical conditions that could be exacerbated by treatment or that would seriously compromise safety assessment or compliance with the protocol, in the judgment of the investigator.
* Women who are pregnant or breastfeeding
* Prior known hypersensitivity reactions to monoclonal antibodies (≥ Grade 3).
* Prior known hypersensitivity reactions to study drugs and/or any of their excipients.
* Patients who have a history of allergy to IMGN632 (or any of its excipients), azacitidine, or venetoclax.
